An exploratory study of fractionated large field proton therapy is proposed. We describe work already performed in the investigation of proton irradiation. This includes investigation of the problems posed by heterogeneity and a description of patients treated by us at the Harvard Cyclotron Laboratory. The objectives of the study are: (1) to evaluate the potential clinical advantages of proton therapy for selected tumor-normal tissue situations through critical evaluation of comparative treatment plans and treatment of selected patients; (2) to assess the problems posed by tissue heterogeneity through theoretical calculations, use of a CT scanner in a variety of anatomic sites, and confirmatory measurements in proton beams; (3) to make improvements to the treatment facility which will permit routine treatment of a substantial number of patients with one fraction per day and with reliability of dose delivery and beam quality; (4) to measure the proton RBE for small fractionated doses with a number of end points; (5) to treat a number of patients with protons in situations in which protons appear to offer an advantage and for which the heterogeneity problem is surmountable; (6) to plan a prospective clinical trial of proton vs photon therapy; and (7) to design these clinical trials, to the extent feasible, to provide control information for work with pi-meson or heavy ion therapy. If this program continues to demonstrate significant advantages for the highly localized dose distributions that can be achieved with proton beams, it will offer the potential for improved local control and/or reduction of morbidity for a large class of cancer patients.